But don't tell that to one of the leaders of the VITAL trial, which is under review for renewal at the NIH this month.

"By no means is the question already answered and this issue settled," JoAnn Manson, MD, DrPH, of Brigham and Women's Hospital in Boston, told MedPage Today.

"VITAL will be highly informative and will move the needle in a major way, whether the results are positive, negative, or neutral," she said. "VITAL will answer the questions that need to be answered about vitamin D, and the trial design is rigorous and of the highest quality and ethical standards."

In addition to the tension associated with NIH grant renewal process, Manson and her colleagues have been adamant in maintaining that the study is well-designed in response to MedPage Today questions about the potential for unblinding when participants undergo routine vitamin D screening by primary care physicians.

The trial aims to show whether supplementation with vitamin D, given at a dose of 2,000 IU of vitamin D3 (cholecalciferol) per day, fish oil (840 mg of marine omega-3 fatty acids per day), or both can stave off the development of cardiovascular disease and cancer in women 55 and older and men 50 and older. And to ensure that none of the participants develop vitamin D deficiency, all are allowed to take supplements up to the recommended dietary allowance of 800 IU per day.

Manson said that VITAL improves on previous trials in several ways.

VITAL is the largest randomized vitamin D supplementation trial in the world, she said, and it is testing a dose and dosing regimen that the researchers believe balances safety and efficacy. Most prior trials evaluated lower doses of vitamin D and administration once a month or even less frequently, which could negatively affect an individual's physiologic response, she said.

The form of vitamin D used in the trial -- vitamin D3 -- also could have an advantage in terms of bioavailability compared with other forms, she said.

In addition, the primary outcomes of VITAL are adjudicated cardiovascular disease and cancer events through 5 years of supplementation. Many of the previous trials had shorter follow-up and had the primary objective of evaluating bone health; other outcomes, including cardiovascular disease, often were not pre-specified and were not validated as thoroughly as in VITAL.

Beyond cardiovascular disease and cancer, VITAL will include ancillary studies looking at the effects of supplementation on several other outcomes, including diabetes, cognitive function, depression, and infection rates.

Another strength, Manson said, is that more than 16,000 participants provided a blood sample at baseline to allow an assessment of serum 25-hydroxyvitamin D levels. Another 4,000 have already provided follow-up blood samples, and it is expected that about 6,000 will eventually provide them.

A final unique aspect of the VITAL trial, she said, is the inclusion of more than 5,000 black participants; other trials have not had that degree of racial/ethnic diversity. Having that many black participants may help answer questions about whether vitamin D supplementation can improve outcomes in that population and whether it can potentially reduce health disparities.

"We believe very strongly that VITAL will answer many important questions, that it remains highly relevant, and that the results could sway the meta-analysis findings," Manson said, noting that the final results are expected early in 2017.

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